Immuno-Positron Emission Tomography with Zirconium-89-Labeled Monoclonal Antibodies in Oncology: What Can We Learn from Initial Clinical Trials?

Abstract

Selection of the right drug for the right patient is a promising approach to increase clinical benefit of targeted therapy with monoclonal antibodies (mAbs). Assessment of in vivo biodistribution and tumor targeting of mAbs to predict toxicity and efficacy is expected to guide individualized treatment and drug development. Molecular imaging with positron emission tomography (PET) using zirconium-89 (89Zr)-labeled monoclonal antibodies also known as 89Zr-immuno-PET, visualizes and quantifies uptake of radiolabeled mAbs. This technique provides a potential imaging biomarker to assess target expression, as well as tumor targeting of mAbs. In this review we summarize results from initial clinical trials with 89Zr-immuno-PET in oncology and discuss technical aspects of trial design. In clinical trials with 89Zr-immuno-PET two requirements should be met for each 89Zr-labeled mAb to realize its full potential. One requirement is that the biodistribution of the 89Zr-labeled mAb (imaging dose) reflects the biodistribution of the drug during treatment (therapeutic dose). Another requirement is that tumor uptake of 89Zr-mAb on PET is primarily driven by specific, antigen-mediated, tumor targeting. Initial trials have contributed toward the development of 89Zr-immuno-PET as an imaging biomarker by showing correlation between uptake of 89Zr-labeled mAbs on PET and target expression levels in biopsies. These results indicate that 89Zr-immuno-PET reflects specific, antigen-mediated binding. 89Zr-immuno-PET was shown to predict toxicity of RIT, but thus far results indicating that toxicity of mAbs or mAb-drug conjugate treatment can be predicted are lacking. So far, one study has shown that molecular imaging combined with early response assessment is able to predict response to treatment with the antibody-drug conjugate trastuzumab-emtansine, in patients with human epithelial growth factor-2 (HER2)-positive breast cancer. Future studies would benefit from a standardized criterion to define positive tumor uptake, possibly supported by quantitative analysis, and validated by linking imaging data with corresponding clinical outcome. Taken together, these results encourage further studies to develop 89Zr-immuno-PET as a predictive imaging biomarker to guide individualized treatment, as well as for potential application in drug development.

In Vivo Targeting and Positron Emission Tomography Imaging of Tumor with Intrinsically Radioactive Metal–Organic Frameworks Nanomaterials

“…To date, there are 11 active, recruiting, or completed clinical trials (search from clinicaltrials.gov) using 89 Zr-labeled antibodies. 43 The time points of 0.5, 2, 20, 24, 48, 72, 96, and 120 h p.i. were chosen for serial PET scans and the coronal slides containing the center of MDA-MB-231 tumor are shown in Figures 3 and S13.…”

Fc-Mediated Anomalous Biodistribution of Therapeutic Antibodies in Immunodeficient Mouse Models

“…In humans, non-lymphoid organs such as the liver show FcγR expression on resident macrophages known as Kupffer cells (35). Thus, the existing clinical practice of performing immunoPET imaging with 89 Zr-labeled antibody tracers after pre-injecting patients with an excess amount (mass) of unlabeled antibody plausibly allows for the in vivo occupancy of FcR sites in non-target organs and improves the in vivo delineation of tumor lesions to yield better tumor-to-background ratios (22, 36). …”

“…The inclusion of noninvasive imaging of disease biomarkers in the design of clinical trials for antibody-based therapeutics can impact clinical outcomes by virtue of the ability of imaging to (i) identify patients who may be eligible for treatment with targeted therapies, (ii) inform the dosing of patients based on the in vivo expression levels of the biomarker, and (iii) evaluate response to treatment (17–19). There has been a surge of reports demonstrating the successful translation of immunoPET tracers in the cancer clinic (20–22). ImmunoPET allows the noninvasive evaluation of disease burden in vivo and facilitates the creation of a companion diagnostic agent to a therapeutic antibody.…”

The Landscape of Clinical Trials Evaluating the Theranostic Role of PET Imaging in Oncology: Insights from an Analysis of ClinicalTrials.gov Database

“…The first necessity is developing a more rational approach to clinical trial design. For example, Humber et al 26 appealed for more randomized trials to demonstrate a clinical benefit of an early tailoring of the induction treatment in breast cancer by PET imaging; Jauw et al 27 also proposed several approaches to evaluating the clinical application of PET imaging to guide individualized treatment. During the design of a trial, clinicians and other relevant parties (e.g., academic institutions, regulators, clinical research organizations) should make concerted efforts to ensure that the trial design reflects the characteristics of a specific condition as well as pertinent clinical questions.…”